Derivatives of lysine and aspartic acid

ABSTRACT

The compounds of formula ##STR1## where R=H and n=1 or R=(C 6  -C 26 )-acyl and n=2 are useful in the treatment of muscular fatigue and muscular contraction in men and animals and also in the stimulation of development in vegetation. 
     The compounds are claimed per se and in pharmaceutical and horticultural compositions. Methods of treatment of men, animals and vegetation are also claimed.

This is a division of application Ser. No. 324,004 filed Nov. 23, 1981.

BACKGROUND OF INVENTION

There has for a long time been a need for a means of counteracting the effects of muscular fatigue and of temporary and involuntary muscular contractions, particularly in connection with sporting activities, wherein such physiological phenomena result from prolonged efforts.

OBJECT OF THE INVENTION

It is an object of the invention to satisfy the aforesaid need.

SUMMARY OF THE INVENTION

We have found that certain derivatives of lysine and aspartic acid have biological properties which counteract the effects of muscular fatigue and of temporary and involuntary muscular contractions. These derivatives, which form our invention, have the formula ##STR2## in which R represents a hydrogen atom and n is 1 or R represents an acyl group having from 6 to 26 carbon atoms and n is 2.

Lysine aspartate (R=H, n=1) may be prepared by the simple reaction of lysine with aspartic acid in an aqueous solution to a pH value of approximately 7. The lysine acyl aspartates (R=acyl, n=2) may be prepared by the total salination of the active amine function of lysine by a lipoamino acid, namely aspartic acid the amine function of which has been acylated by a compound containing an acyl group having from 6 to 26 carbon atoms.

In the lysine acyl aspartates, the acyl group may be saturated or unsaturated and may have a straight or branched chain. The acyl group is preferably selected from the group consisting of caproyl, capryl, lauryl, palmityl, undecenyl, oleyl and linoleyl groups.

The compounds of the invention are useful as the active ingredient of pharmaceutical compositions for topical application to men and animals and in methods of treating muscular fatigue and muscular contraction in men and animals by topical application. The compositions preferably contain from 0.5 to 10% by weight of the active ingredient.

We have further and surprisingly found that the compounds of the invention are of horticultural use in stimulating the development of vegetation, particularly in the germination of seeds and in the treatment of leaves, the latter evidenced by a change in the intensity of the green colouration of the leaves upon such treatment. Our invention therefore encompasses the new compounds, pharmaceutical and horticultural compositions containing them, and methods of treating men and animals against muscular fatigue and muscular contraction and of treating vegetation to stimulate its development.

DETAILED DESCRIPTION OF THE INVENTION

                  TABLE 1                                                          ______________________________________                                         Type of  Molecular Acid     Theoretical                                                                            Actual                                     Derivative                                                                              weight    index    Nitrogen                                                                               Nitrogen                                   ______________________________________                                         Lysine   279       0        15%     14.7%                                      aspartate                                                                      Lysine   551       0        12.7%   12.4%                                      capryl                                                                         aspartate                                                                      Lysine   663       0        10.5%   10.1%                                      Palmitic                                                                       aspartate                                                                      Lysine   607       0        11.5%   11.3%                                      Lauric                                                                         aspartate                                                                      ______________________________________                                    

Table 2 shows the results obtained in the treatment of muscular fatigue and the muscular decontraction effects obtained using lysine aspartate. Comparison is made with other aspartates.

                  TABLE 2                                                          ______________________________________                                         Physiological                                                                           Lysine    Arginine  Ornithine                                                                             Guanidine                                  Reaction aspartate aspartate aspartate                                                                             aspartate                                  ______________________________________                                         Relaxing very      slight    slight none                                       effect   marked                                                                Muscular very      none      none   none                                       decontraction                                                                           marked                                                                effect,                                                                        involuntary                                                                             very rapid                                                            or after                                                                       effort                                                                         ______________________________________                                    

As can be seen, the effectiveness is due to the assocation of the aspartic acid with the lysine. The aspartates of the two other basic amino acids, arginine and ornithine, and of quanidine have little or no effect. Table 3 shows the results obtained with various lysine acyl aspartates.

                  TABLE 3                                                          ______________________________________                                         Effects  Nature of the acyl chain                                              obtained Acetyl   Butyl   Capryl  Lauryl                                                                               Palmityl                               ______________________________________                                         Relaxation of                                                                           None     none    very    very  very                                   lower limbs               marked  marked                                                                               marked                                 Effect on                                                                               None     none    rapid   rapid rapid                                  muscular                                                                       decontraction                                                                  ______________________________________                                    

It can be seen that lysine lower acyl aspartates are ineffective, whereas the lysine higher acyl aspartates according to the invention are notably effective.

The following formulations are examples of suitable pharmaceutical compositions according to the invention.

    ______________________________________                                         1.      Stearic acid           5                                                       Cetyl polyoxyethylene alcohol                                                                        10                                                       Isopropyl palmitate   10                                                       Glycerol              10                                                       Lysine aspartate       1 to 10                                                 Water to make up to 100                                                2.      Glycerol stearate      5                                                       Beeswax               10                                                       Vaseline oil          10                                                       Sorbitol polyoxyethylene oleate                                                                       5                                                       Glycerol              10                                                       Lysine capryl aspartate                                                                               1 to 10                                                 Water to make up to 100                                                3.      Stearic acid           5                                                       Cetyl polyethylene alcohol                                                                           10                                                       Ethyl stearate        10                                                       Glycerol              10                                                       Lysine palmityl aspartate                                                                             1 to 10                                                 Water to make up to 100                                                ______________________________________                                    

The following formulations are examples of suitable horticultural compositions according to the invention.

    ______________________________________                                         (a) for the treatment of leaves                                                1        Lysine aspartate    1 to 5                                                     Water to make up to 100                                               2.       Lysine capryl aspartate                                                                            1 to 5                                                     Water to make up to 100                                               3.       Lysine lauryl aspartate                                                                            1 to 5                                                     Water to make up to 100                                               4.       Unidecenyl aspartate                                                                               1 to 5                                                     Water to make up to 100                                               (b) for the treatment of seeds                                                 1.       Lysine aspartate    0.5 to 10                                                  Bentonite (Fullers earth)                                                      to make up to 100                                                     2.       Lysine capryl aspartate                                                                            0.5 to 10                                                  Sodium lauryl collagenate                                                                          5                                                          Water to make up to 100                                               3.       Lysine capryl aspartate                                                                            0.5 to 10                                                  Bentonite (Fullers earth)                                                      to make up to 100                                                     ______________________________________                                     

We claim:
 1. A method of treating muscular fatigue or muscular contraction in a man or animal comprising the topical application in a pharmaceutically acceptable carrier of an amount sufficient to treat muscular fatigue or muscular contraction of a compound which is a derivative of lysine and aspartic acid having the general formula ##STR3## in which R represents a hydrogen atom and n is 1 or R represents an acyl group having from 6 to 26 carbon atoms and n is 2 and in which the acyl group is derived from an aliphatic moncarboxylic acid.
 2. The method of claim 1 wherein the said compound is present in the amount of from about 0.5 to about 10% by weight of the combination of the said carrier and the said compound.
 3. A method of treating muscular fatigue or muscular contraction in a man or animal comprising the topical application in a pharmaceutically acceptable carrier of an amount sufficient to treat muscular fatigue or muscular contraction of a compound which is a derivative of lysine and aspartic acid having the general formula ##STR4## in which R represents a hydrogen atom and n is 1 or R represents an acyl group having from 6 to 26 carbon atoms and n is 2 and in which the acyl group is derived from an aliphatic moncarboxylic acid wherein the aliphatic monocarboxylic acid is selected from the group consisting of caproyl, capryl, lauryl, palmityl, undecenyl, oleyl and linoleyl groups.
 4. The method of claim 1 wherein the said compound is present in the amount of from about 0.5 to about 10% by weight of the combination of the said carrier and the said compound.
 5. A method of treating muscular fatigue or muscular contraction in a man or animal comprising the topical application in a pharmaceutically acceptable carrier of an amount sufficient to treat muscular fatigue or muscular contraction of lysine aspartate.
 6. The method of claim 5 wherein the said lysine aspartate is present in the amount of from about 0.5 to about 10% by weight of the combination of the said carrier and the said lysine aspartate.
 7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound, the compound being present in an amount sufficient to treat muscular fatigue or muscular contraction, the compound being a derivative of lysine and aspartic acid having the general formula ##STR5## in which R represents a hydrogen atom and n is 1 or R represents an acyl group having from 6 to 26 carbon atoms and n is 2 and in which the acyl group is derived from an aliphatic monocarboxylic acid.
 8. The pharmaceutical composition of claim 7 wherein the said compound is present in the amount of from about 0.5 to about 10% by weight of the combination of the said carrier and the said compound. 